A desirable approach to control AIDS would be to develop a vaccine that could confer long-term immunity against the human immunodeficiency virus (HIV) and at the same time be easily administered worldwide. We have identified two highly antigenic vaccinia virus proteins of 14K and 39K and shown that, when we covalently link 14K to HIV-1 env or gag and expressed the fusion proteins in cells infected with HIV-vaccinia virus recombinants we observe the following: 1) the fusion proteins are localized on the cell surface in the form of oligomers, 2) are not cleaved or released from the cells, 3) env is poorly glycosylated and 4) when the recombinant viruses are inoculated in mice there is induction of specific antibodies against HIV env and gag. The safety of these HIVvaccinia virus recombinants was further assesed in immunosuppressed mice. In light of the uniqueness of the 14K-fusion protein, we suggest that HIV-vaccinia fusion proteins may provide an effective means of enhancing and modifying B and T-cell responses against HIV infection. The goal of this proposal is to determine whether the immune response elicited by HIV-vaccinia fusion proteins is more effective against HIV than the immune response elicited by the native proteins. We will use the mouse model because it will provide a wider range of data that otherwise we could not practically obtain from a primate model. The long-term objective of this study is to develop a safe vaccine that can be tested in primates and eventually in humans. The proposed project will consist of the following main objectives: 1. To construct HIV-vaccinia recombinant viruses (wild type and attenuated) expressing fusion proteins containing the full-length sequence of vaccinia 14K or 39K proteins fused to complete or partial sequence of HIV-1 env and gag and study their mode of expression in cultured cells. 2. To characterize the extent of the humoral immune response elicited in mice primed with HIV-vaccinia recombinant viruses and boosted with either the live recombinant virus, purified non-fused or purified fused proteins and to define the mode of inhibition of HIV cytopathogenicity by the specific antisera. 3. To characterize the extent of the cellular immune response in mice of different haplotype immunized as described in objective 2. If the fusion proteins elicit a more effective and sustained humoral and cellular immune response to HIV antigens than the non-fused proteins, then this novel approach may produce a useful vaccine against HIV to be used in either seronegative (as a preventive measure) or seropositive human subjects (as therapeutic agent).